Low dose temazepam

ABSTRACT

This invention relates to a hard gelatin capsule containing no more than 5 to 10 milligrams of crystalline temazepam and its use in the treatment of transient insomnia.

This is a continuation of application Ser. No. 07/434,142, filed Nov. 9,1989, now abandoned which in turn is a continuation of application Ser.No. 07/295,332, filed Jan. 10, 1989, now abandoned, which in turn is acontinuation of application Ser. No. 06/910,571, filed Sept. 23, 1986,now abandoned.

This invention relates to a new pharmaceutical form of temazepam and itsuse as a hypnotic agent.

More particularly, it relates to a low dose hard gelatin temazepamcapsule and its use in the treatment of insomnia, especially, transientinsomnia.

Temazepam, whose chemical name is7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneis a well known hypnotic agent used in the treatment of insomnia. Thecommercial product is sold in the United States in the form of hardgelatin capsules containing 15 and 30 milligrams of temazepam. Softgelatin capsules containing 10 and 20 milligrams of temazepam are alsoavailable abroad. The hard gelatin capsule has been studied in greatdepth and has been found to be generally effective at doses of 15 and 30milligrams of temazepam. At doses of 10 and 20 milligrams, the softgelatin capsules have also been found to be effective, althoughNicholson, et al. (Br. J. Clin. Pharmac., 3,543-550,1976) have reportedthat at 10 milligrams, no change in total sleep time was found, whereasat 20 milligrams, total sleep time was markedly increased. Lower doseforms of temazepam containing 5 milligrams of the compound have beenused in a number of investigations (LaReforma Medica, 16,425-427, 1970;Bombay Hosp. J., 16,222-223,1974; Neuropsychobiology 9(1),52-65,1983)but have never been found to be useful in treating insomnia. In theNeuropsychobiology publication, the authors indicate that at 5milligrams, temazepam is known to be of no clinical importance as ahypnotic agent.

Although the side effects of temazepam are minimal, the lowest effectivedose of the product would be desirable. It would be especially useful intreating transient insomnia, which occurs in healthy individuals whosesleep pattern has been temporarily disrupted, for example by airplanetravel or by changing work shifts. It has now been found that a hardgelatin capsule comprising up to 10 milligrams of temazepam, in whichthe temazepam particles have a specific surface area of from 0.65 to 1.1square meters per gram (m² /g) and 95% of the particles have a particlesize diameter of less than 65 microns (u), is effective in the treatmentof insomnia, especially in improving sleep latency. Preferably thecapsule contains the temazepam in amounts of from 5 to 10 milligrams,more preferably 6 to 8 milligrams, especially 7.5 milligrams, incombination with a pharmaceutically acceptable carrier. The capsule isnormally administered just before bedtime.

Crystalline temazepam can be synthesized with a purity of not less than98% using known procedures such as that disclosed in U.S. Pat. No.3,296,245. The bulk temazepam is milled to obtain the required particlesize and surface area with an Alpine 160 UPZ mill using a stainlesssteel pin. The particle size is determined using a Malverne ParticleSizer, Model 3600 E equipped with a 14.3 mm flow cell and a 100 mm lens.Surface area measurements are made essentially in accordance with thestandard B.E.T. procedure of Brunauer, Emmet and Teller (J. Am. Chem.Soc. 59, 2682, 1937 and J. Am. Chem. Soc., 60, 309, 1938). The temazepamis formulated with standard hard gelatin capsule excipients andencapsulated in conventional hard gelatin capsules using knownprocedures.

The use of low dose temazepam hard gelatin capsules in the treatment oftransient insomnia was evaluated in a double blind, parallel group,placebo-controlled sleep laboratory study using 201 healthy subjects.Just before bedtime each subject was given a capsule containing placebo,or 7.5, 15 or 30 milligrams of temazepam. The number of subjects in thefour treatment groups were placebo -- 50; 7.5 milligrams -- 51; 15milligrams -- 49; and 30 milligrams -- 51. Testing was carried out overa period of one night in the sleep laboratory. The key parameters ofsleep latency and total sleep time were among those measured by EEGanalysis (polysomnography). The mean values for sleep latency and totalsleep-time obtained with each treatment group were as follows:

    ______________________________________                                        Group   Sleep Latency (min.)                                                                         Total Sleep Time (min.)                                ______________________________________                                        Placebo 37             411                                                    7.5 m.g.                                                                              26             422                                                    15 m.g. 22             429                                                    30 m.g. 18             441                                                    ______________________________________                                    

As can be seen from the above data 7.5 milligrams of temazepam waseffective in reducing both sleep latency and increasing total sleep timein the study. The most unexpected result is that the effect occurred asthe dosage dropped below the 15 milligram dosage level. The usualeffect-no effect results, which would have been expected between 7.5 and15 milligrams of temazepam based on previous hard gelatin capsulestudies did not occur.

EXAMPLE 1

White crystalline temazepam having a purity of not less than 98% isprepared according to the procedure described in U.S. Pat. No.3,296,245. The bulk temazepam obtained is fed into an Alpine 160 UPZmill with a stainless steel pin at a rate of about 40 kilograms (kg) perhour using a mill speed of about 11,000 RPM to obtain temazepamparticles having a specific surface area of 0.65 to 1.1 m² /g area and95% of the particles having a particle size diameter of less than 65 u.The surface area measurement is made with the Quantector Gas Flow Systemand Quantasorb Surface Area Analyser at the temperature of liquidnitrogen (-196° C.) using krypton as the absorbant and helium as thecarrier gas. The particle size diameter is determined with the MalverneParticle Sizer at an obscuration value of 0.2 to 0.25 using a 0.1% Tween80 solution in water saturated with temazepam in which 1 to 2 grams oftemazepam sample to be tested has been dispersed. After the feed rateand mill speed of the Alpine mill have been set, they are monitored atregular intervals to maintain the required particle size and surfacearea.

EXAMPLE 2

To prepare hard gelatin capsules containing 7.5 milligrams of thetemazepam of example 1, 12 kg of temazepam and 12 kg. of lactose arepassed through an 18 mesh screen. This mixture is added to 372 kg oflactose, which has also been passed through an 18 mesh screen, and 4 kgof magnesium stearate in a 30 cu. ft. PK Mixer without an intensity bar.The capsule ingredients are mixed for 30 minutes using tumbling actiononly. The capsule mix is encapsulated in number 3 Lock hard gelatincapsules with opaque blue caps and opaque pink bodies, and the capsulesare then passed through a capsule polisher. Each capsule contains 250milligrams of capsule mix and 7.5 milligrams of temazepam.

I claim:
 1. A method of treating transient insomnia with temazepam in ahuman in need of said treatment the improvement which consistingessentially of the step of administering to said human a hard gelatincapsule containing not more than 5 to 10 milligrams of crystallinetemazepam having a surface area of from 0.65 to 1.1 m² /g and 95% of thetemazepam having particle size diameters of less than 65 microns.
 2. Amethod according to claim 1, in which 6 to 8 milligrams of temazepam areadministered.
 3. A method according to claim 1 in which 7.5 milligramsof temazepam are administered.